The present invention pertains at least in part to cancer treatment, certain chemical compounds, and methods of treating tumors and cancers with the compounds.
RON (recepteur d'origine nantais) is a receptor tyrosine kinase that is part of the MET proto-oncogene family. It is activated by binding to its natural ligand MSP and signals via the PI3K and MAPK pathways. RON can be deregulated in cancer by mechanisms such as over-expression of the receptor and/or the presence of constitutively active splice variants. Inhibition of RON has been shown to lead to a decrease in proliferation, induction of apoptosis and affects cell metastasis. RON overexpression is observed in a variety of human cancers and exhibits increased expression with progression of the disease.
MET (also known as Met, c-Met, cMet) is a receptor tyrosine kinase that is a heterodimeric protein comprising of a 50 kDa α-subunit and a 145 kDa β-subunit (Maggiora et al., J. Cell Physiol., 173:183-186, 1997). It is activated by binding to its natural ligand HGF (hepatocyte growth factor, also known as scatter factor) and signals via the PI3K and MAPK pathways. MET can be deregulated in cancer by mechanisms such as autocrine/paracrine HGF activation, over-expression of the receptor, and/or the presence of activating mutations. Significant expression of MET has been observed in a variety of human tumors, such as colon, lung, prostate (including bone metastases), gastric, renal, HCC, ovarian, breast, ESCC, and melanoma (Maulik et al., Cytokine & Growth Factor Reviews, 13:41-59, 2002). MET is also implicated in atherosclerosis and lung fibrosis. Inhibition of MET can cause a decrease in cell motility, proliferation and metastasis, as reviewed in, e.g., Chemical & Engineering News 2007, 85 (34), 15-23.
Elevated expression of MET has been detected in numerous cancers including lung, breast, colorectal, prostate, pancreatic, head and neck, gastric, hepatocellular, ovarian, renal, glioma, melanoma, and some sarcomas. See Christensen et al., Cancer Letters, 225(1):1-26 (2005); Comoglio et al., Nature Reviews Drug Disc., 7(6):504-516 (2008). MET gene amplification and resulting overexpression has been reported in gastric and colorectal cancer. Smolen et al., Proc. Natl. Acad. Sci. USA, 103(7):2316-2321 (2006); Zeng et al., Cancer Letters, 265(2):258-269 (2008). Taken together, the MET proto-oncogene has a role in human cancer and its over-expression correlates with poor prognosis. Abrogation of MET function with small molecule inhibitors, anti-MET antibodies or anti-HGF antibodies in preclinical xenograft model systems has shown impact when MET signaling serves as the main driver for proliferation and cell survival. Comoglio et al., Nature Reviews Drug Disc., 7(6):504-516 (2008); Comoglio et al., Cancer & Metastasis Reviews, 27(1):85-94 (2008).
As human cancers progress to a more invasive, metastatic state, multiple signaling programs regulating cell survival and migration programs are observed depending on cell and tissue contexts. Gupta et al., Cell, 127:679-695 (2006). Recent data highlight the transdifferentiation of epithelial cancer cells to a more mesenchymal-like state, a process resembling epithelial-mesenchymal transition (EMT) (Oft et al., Genes & Dev., 10:2462-2477 (1996); Perl et al., Nature, 392:190-193 (1998)) to facilitate cell invasion and metastasis. Brabletz et al., Nature Rev., 5:744-749 (2005); Christofori, Nature, 41:444-450 (2006). Through EMT-like transitions mesenchymal-like tumor cells are thought to gain migratory capacity at the expense of proliferative potential. A mesenchymal-epithelial transition (MET) has been postulated to regenerate a more proliferative state and allow macrometastases resembling the primary tumor to form at distant sites. Thiery, Nature Rev. Cancer, 2(6):442-454 (2002). MET and RON kinases have been shown to play a role in the EMT process. Camp et al., Cancer, 109(6):1030-1039 (2007); Grotegut et al., EMBO J., 25(15):3534-3545 (2006); Wang et al., Oncogene, 23(9):1668-1680 (2004). It has been documented in vitro that RON and MET can form heterodimers and signal via such RON-MET dimers.
MET and RON are known to interact and influence the activation of one another. Furthermore, co-expression of the two receptors, when compared to each receptor alone, is associated with the poorest clinical prognosis in bladder, CRC, and breast cancer patients. Since co-expression of RON and MET in cancer has been observed, such “cross-talk” may contribute to tumor growth.
ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase that belongs to the insulin receptor subfamily. Constitutively active fusion proteins, activating mutations, or gene amplifications have been identified in various cancers, for example, kinase domain mutations in Neuroblastoma (Eng C., Nature, 2008, 455, 883-884), echinoderm microtubule-associated protein-like 4 (EML4) gene-ALK fusion in non-small cell lung cancer (NSCLC) (Soda M. et al., Nature, 2007, 448, 561-566), TPM3 and TPM4-ALK fusions in inflammatory myofibroblastic tumors (IMT) (Lawrence B. et al., Am. J. Pathol., 2000, 157, 377-384), and nucleophosmin (NPM)-ALK fusions in anaplastic large cell lymphomas (ALCL) (Morris S. W. et al., Science, 1994, 263, 1281-1284). Cell lines harboring such mutations or fusion proteins have been shown to be sensitive to ALK inhibition (McDermott U. et al., Cancer Res., 2008, 68, 3389-3395).
The following documents are also noted: WO10/104,945; WO10/059,771; WO10/039,248; WO09/140,549; WO09/094,123; WO08/124,849; WO08/53157; WO08/051,808; WO08/051,805; WO08/039,457; WO08/008,539; WO07/138,472; WO07/132,308; WO07/075,567; WO07/067,537; WO07/064,797; WO07/002,433; WO07/002,325; WO05/062795; WO05/010005; WO05/004607; WO03/82868; U.S. Pat. No. 7,585,876; U.S. Pat. No. 7,452,993; U.S. Pat. No. 7,259,154; U.S. Pat. No. 7,230,098; U.S. Pat. No. 6,235,769; US2010/256365; US2010/063031; US2009/143352; US2009/076046; US2009/005378; US2009/005356; US2008/293769; US2008/221197; US2008/221148; US2008/167338; US2007/032519; US2007/287711; US2007/123535; US2007/072874; US2007/066641; US2007/060633; US2007/049615; US2007/043068; US2007/032519; US2006/178374; US2006/128724; US2006/046991; US2005/182060; US2004/116488; U.S. Appl. No. 61/334,690 (filed May 14, 2010); Wang et al., J. Appl. Poly. Sci., 109(5), 3369-3375 (2008); Zou et al., Cancer Res., 67(9), 4408 (2007); Arteaga, Nature Medicine, 13, 6, 675 (June 2007); Engelman, Science, 316, 1039 (May 2007); Saucier, PNAS, 101, 2345 (February 2004).
There is a need for effective therapies for use in proliferative disease, including treatments for primary cancers, prevention of metastatic disease, and targeted therapies, including receptor tyrosine kinase inhibitors, such MET, RON, and ALK inhibitors, dual and multi-target inhibitors, including selective inhibitors (such as selectivity over Aurora kinase B (AKB) and/or KDR), and for potent, orally bioavailable, and efficacious inhibitors, and inhibitors that maintain sensitivity of epithelial cells to epithelial cell directed therapies.